Corrole Nanoparticles for Chemotherapy of Castration-Resistant Prostate Cancer and as Sonodynamic Agents for Pancreatic Cancer Treatment

A nanoparticle-based system, composed of the gallium(III) complex of a minimally substituted corrole that is coated by transferrin as a targeting vehicle (3-Ga NPs), has been used for pre-clinical evaluation of its efficacy against human metastatic castration-resistant prostate cancer (mCRPC) tumor xenografts. All mice (N = 9) responded to a dose of 10 mg/kg, with a remarkable tumor growth inhibition of 400% following 2 weeks of treatment; Ames and hERG tests excluded potential concerns regarding mutagenicity and cardiotoxicity, respectively. Also demonstrated is the potential application of these 3-Ga NPs as sonodynamic agents for the preclinical treatment of pancreatic cancer. 10 mg/kg 3-Ga NPs combined with exposure to ultrasound waves (2 min of 1 MHz 0.1 w/cm2 twice a week) induced up to 77% tumor shrinkage. Consistently, tumor/tissue distribution and serum levels of 3-Ga NPs in mice revealed high tumor specificity, favorable pharmacokinetics, fast absorption, slower redistribution, and very slow drug clearance.


Table of Contents
3-Ga NPs PK analysis S3

Figure S2
Xenograft model of nude mice (Foxn1 nu ) implanted with DU-145 hormone refractive castration resistance cell line tumors. S4

Figure S3
Body Weight mesurments of Xenpgraft prostate cancer model experiments S5 Figure S4 Reprasentative images of tumor bearing nude mice at end of the experiment before euthanization S6 Table S1 Individual tumor histological evaluation S7 Figure  Specificity of 3-Ga NPs S11 Figure S9 AMES MPF S12 Figure  S10 The effects of test items on hERG tail currents S13 Figure  S11 Structure and formulation assessments of 3-Ga NPs S14 Figure  S12 1 H NMR spectrum of 3-Ga in CDCl 3 . Asterisk represents the solvent peak. S15 Figure  S13 19 F NMR spectrum of 3-Ga in CDCl 3 . S16 Figure  S14 HPLC chromatogram (column: C18 silica gel, flow rate: 1 mL/min, eluent: MeOH:water = 88:12, pH 7.4) of 3-Ga S17

4-Ga NPs + US
Control +US  (3)Ga NPs with and without ultrasound exposure relative to Control (with and without ultrasound); and (B) 5 mg/Kg of (3)Ga NPs with and without ultrasound exposure relative to Control (with and without ultrasound). Tumors were measured for width (W) and length (L) using caliper and volume (V) was calculated according to the following equation: V=LW2/2, data was normalized (relative to initial tumor size at day 5) and plotted. Results represent mean ±SEM of all mice in each group (n=7). (C) Changes in body weight (gr) during the study. Data was plotted as percentage of change, relative to the initial weight. Results represent mean ±SEM of all mice in each group. Figure S8 Specificity of 3-Ga NPs: NSG mice bearing human Panc-1 tumors ( 65 cubic mm) received a single IV injection of either 3-Ga NPs (T, ROI 1, 5 mg/Kg) or Vehicle (C, ROI 1, roughly 120 μL) and were imaged at 2.5 hr post injection using a noninvasive small animal fluorescence imaging system. ROI desclose estimation of fluorescnece intensity at each treated mice within the enclosed ROI.   MeOH:water = 88:12, pH 7.4) of 3-Ga. Inset shows the UV/vis spectrum corresponding to the peak.

Tf coated NPs formulation
A solution of 100 µL of 1 mM corrole dissolved in DMSO was added under vigorous stirring to 800 μL of deionized water (in a glass vial) using a 50 μL Hamilton syringe with the needle tip placed close to the micro stirring bar. Standard magnetic stirrer plates were used. No sign of precipitation was observed. Stirring of the solution has ciest and after 1 min of incubation, 100 µL of Tf 100 μM in PBS, pH 7.2 was added to the solution. Solutions were incubated for 30 min at 5 °C and transferred to dialysis tubing for 24 h dialysis in a 1 L PBS solution. Dialysis tubes were purchased from Spectrum labs, cat. No. 3787-D20; type: RC; MWCO: 12-14000. Dialysis tubing was treated vigorously with EDTA: tubing was immersed in 1 L of 2% sodium bicarbonate/1 mM EDTA solution in a 2 L glass beaker. Tubing was rinsed thoroughly with ddH2O (sterile ultra-pure water) and submerged completely in 50% ethanol/1 mM EDTA and stored at 4 °C. Tubing was rinsed thoroughly before use.